- Correspondence: Paul Proost, Laboratory of Molecular Immunology, Rega Institute, K.U.Leuven, Minderbroedersstraat 10, 3000 Leuven. E-mail:
Background During the first line defense of an infected host, circulating neutrophils invade the inflamed tissue, whereas mature neutrophils from the bone marrow pool migrate toward the blood circulation to reinforce tissue infiltration. The CXC chemokine CXCL8/interleukin-8 (IL-8) is a potent attractant of neutrophils. Recently, we discovered a new natural posttranslational modification of CXCL8, i.e. the deimination of Arg into citrulline by peptidylarginine deiminases.
Design and Methods The ability to provoke leukocytosis was assessed by intravenous administration of citrullinated CXCL8 in rabbits. Absorption of citrullinated CXCL8 to the Duffy antigen/receptor for chemokines (DARC) on human or rabbit erythrocytes was evaluated using a competitive binding assay. Finally, surface expression of adhesion molecules was studied after stimulating neutrophils with citrullinated CXCL8.
Results Citrullination of CXCL8 significantly increased its ability to recruit neutrophils into the blood circulation. In addition, the competitive binding properties of CXCL8 for DARC were impaired upon citrullination. Since DARC is an important scavenging receptor for CXCL8 in the blood stream, citrullination may delay CXCL8 clearance from the circulation. Furthermore, the shedding of CD62L (L-selectin) and the upregulation of CD11b (α2-integrin) protein expression on CXCL8-induced neutrophils were improved by deimination of CXCL8, possibly contributing to the neutrophil egress from the bone marrow. Conversely, surface expression of CD15, the neutrophilic ligand of endothelial selectins, was equally well upregulated by intact and citrullinated CXCL8.
Conclusions These data show that citrullination of CXCL8 enhances leukocytosis, possibly explained by impaired chemokine clearance from the blood flow and prolonged presentation to the bone marrow.
- Received December 29, 2008.
- Revision received May 12, 2009.
- Accepted May 13, 2009.
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